HIV-1 Vif-mediated ubiquitination/degradation of APOBEC3G involves four critical lysine residues in its C-terminal domain
- 17 November 2009
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences
- Vol. 106 (46), 19539-19544
- https://doi.org/10.1073/pnas.0906652106
Abstract
During coevolution with the host, HIV-1 developed the ability to hijack the cellular ubiquitin/proteasome degradation pathway to counteract the antiviral activity of APOBEC3G (A3G), a host cytidine deaminase that can block HIV-1 replication. Abrogation of A3G function involves the HIV-1 Vif protein, which binds A3G and serves as an adapter molecule to recruit A3G to a Cullin5-based E3 ubiquitin ligase complex. Structure-guided mutagenesis of A3G focused on the 14 most surface-exposed Lys residues allowed us to identify four Lys residues (Lys-297, 301, 303, and 334) that are required for Vif-mediated A3G ubiquitination and degradation. Substitution of Arg for these residues confers Vif resistance and restores A3G's antiviral activity in the presence of Vif. In our model, the critical four Lys residues cluster at the C terminus, opposite to the known N-terminal Vif-interaction region in the protein. Thus, spatial constraints imposed by the E3 ligase complex may be an important determinant in Vif-dependent A3G ubiquitination.Keywords
This publication has 48 references indexed in Scilit:
- Regulation of APOBEC3 Proteins by a Novel YXXL Motif in Human Immunodeficiency Virus Type 1 Vif and Simian Immunodeficiency Virus SIVagm VifJournal of Virology, 2009
- Structure, interaction and real-time monitoring of the enzymatic reaction of wild-type APOBEC3GThe EMBO Journal, 2009
- APOBEC3G Inhibits Elongation of HIV-1 Reverse TranscriptsPLoS Pathogens, 2008
- Model Structure of Human APOBEC3GPLOS ONE, 2007
- Messenger RNA editing in mammals: new members of the APOBEC family seeking roles in the family businessTrends in Genetics, 2003
- Structural Basis for Phosphodependent Substrate Selection and Orientation by the SCFCdc4 Ubiquitin LigaseCell, 2003
- Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif proteinNature, 2002
- Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complexNature, 2002
- Smad3 recruits the anaphase-promoting complex for ubiquitination and degradation of SnoNGenes & Development, 2001
- Mechanisms Underlying UbiquitinationAnnual Review of Biochemistry, 2001